This invention relates to pharmaceutical compositions containing opioids and opioid antagonists, in particular, prodrugs of 3-hydroxymorphinans, suitable for buccal, nasal or sublingual administration and methods of using prodrugs of 3-hydroxymorphinans for buccal, nasal or sublingual administration.
The oral administration of many 3-hydroxymorphinans including nalbuphine, naltrexone, naloxone, nalmefene, morphine, butorphanol, oxymorphone, hydromorphone, levorphanol, levallorphan, buprenorphine and etorphine, will elicit a substantially lesser response as compared to an equal dosage administered parenterally. This reduction in potency most commonly results from the extensive metabolism of the drug during its transit from the gastrointestinal tract to the general circulation. For example, the liver and intestinal mucosa, through which an orally administered drug passes before it enters the circulatory system, are very active enzymatically and can thus metabolize the drug in many ways.
When an orally administered drug is metabolized rapidly by the gastrointestinal system or liver prior to entering the general circulation, its bioavailability is low. This problem can be circumvented by administering the drug by another route. Examples of such alternative routes include buccal, nasal or sublingual. Drugs administered by these routes avoid hepatic and gut-wall metabolism, resulting in increased bioavailability and potency compared to oral administration.
Although 3-hydroxymorphinans are well absorbed from the buccal cavity, many of these compounds have a bitter taste which makes them difficult to administer by that route. The present invention relates to prodrugs of 3-hydroxymorphinans which are devoid of any taste, and are thus more suitable for buccal, sublingual, or nasal administration. Either rapid absorption and decline of plasma drug concentrations or prolonged plasma concentrations of active drug can be achieved by selecting prodrugs with appropriate solubility and hydrolysis rates. These can be formulated as tablets, gels, pastes, patches, or lozenges.
Several 3-hydroxymorphinans having various substituents on the nitrogen atom have been found to exhibit narcotic antagonist as well as narcotic analgesic activity. Such compounds are referred to as agonist-antagonists. Pachter and Matossian in U.S. Pat. No. 3,393,197, issued July 16, 1968, disclose N-substituted-14-hydroxydihydronormorphines, including the N-cyclobutylmethyl derivative, commonly called nalbuphine. Monkovik and Thomas, U.S. Pat. No. 3,775,414, disclose N-cyclobutylmethyl-3,14-dihydroxymorphinan, commonly called butorphanol. Bentley et al., U.S. Pat. No. 3,433,791, disclose 17-(cyclopropylmethyl)-.alpha.-(1,1-dimethylethyl)4,5-epoxy-18,19-dihydro- 3-hydroxy-6-methoxy-.alpha.-methyl-6,14-ethenomorphinan-7-methanol, commonly called buprenorphine.
Still other N-substituted morphinan derivatives are pure narcotic antagonists with little or no agonist activity. Lewenstein, in U.S. Pat. No. 3,254,088, issued May 31, 1966, discloses N-allyl-7,8-dihydro-14-hydroxynormorphinone, commonly known as naloxone. Blumberg, Pachter, and Matossian, in U.S. Pat. No. 3,332,950, issued July 25, 1967, disclose N-substituted-14-hydroxy-dihydronormorphinones, including the N-cyclopropylmethyl analog, commonly known as naltrexone.
Morphine, oxymorphone, hydromorphone and levorphanol are well known 3-hydroxymorphinan analgesics.
A number of references disclose buccal, sublingual or nasal administration of opioids. G. F. Blane et al., in Internatinal Conference on Radioactive Isotopes in Pharmacology, 1969, disclose the absorption of etorphine and dihydromorphine from the buccal cavity. M. D. D. Bell et al., in The Lancet, 1 (8420), 71-73, 1985 disclose buccal administration of morphine sulfate. R. S. Todd in GB 2,100,985, published Jan. 12, 1983, discloses a pharmaceutical composition for the sublingual administration of buprenorphine and salts thereof. H. Lowey in U.S. Pat. No. 4,259,314, issued Mar. 31, 1981, discloses a lozenge for buccal administration containing dextromethorphan. A. A. Hussain in U.S. Pat. No. 4,464,378, issued Aug. 7, 1984, discloses a method of intranasal administration of narcotic antagonists and analgesics, including naloxone, naltrexone, nalbuphine, levorphanol, buprenorphine, and butorphanol, and novel dosage forms containing those compounds which are adapted for nasal administration.
A number of other references disclose formulations and delivery systems for buccal administration, including R. Cournut and G. Gaussens in U.S. Pat. No. 4,020,558, issued May 3, 1977; W. R. Porter in U.S. Pat. No. 4,229,447, issued Oct. 21, 1980; A. G. Tsuk in U.S. Pat. No. 3,972,995 issued Aug. 3, 1976, H. Lowey and H. H. Stafford in U.S. Pat. No. 3,870,790 issued Mar. 11, 1975, H. S. Russell in U.S. Pat. No. 3,444,858 issued May 20, 1969, A. Halpern and C. H. Bradney in U.S. Pat. No. 2,698,822 issued Jan. 4, 1955, L. Geller et al., in U.S. Pat. No. 3,632,743 issued Jan. 4, 1972 and T. Kissel and R. Bergauer in UK patent application GB 2,108,841A published May 25, 1983.
A. A. Hussain in U.S. Pat. No. 4,315,925, issued Feb. 16, 1982 discloses nasal administration of natural female sex hormones.
Bender et al., in U.S. Pat. No. 4,539,315, issued Sept. 3, 1985, disclose an aspirin composition for sublingual administration. A. F. Libby in U.S. Pat. No. 4,432,975 issued Feb. 21, 1984 discloses a microlozenge containing vitamin B-12 for sublingual administration.